P1632: HEREDITARY HEMORRHAGIC TELANGIECTASIA: A COMPREHENSIVE FAMILY STUDY AND A NEW PATHOGENIC VARIANT IN ACVRL1 GENE.
Authors: Alba María Casado Prieto, Joel Martín Padrón, Manuela Moreno Higueras, Susana García Linares
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant disease with an estimated prevalence of 1:5000, although it is probably underdiagnosed. It is characterized by clinically significant vascular malformations (VM), resulting in bleeding manifestations and complications from shunting through VM. The most common symptom is epistaxis, with an age-related expression. The definite diagnosis can be made using the Curaçao clinical criteria or by identification of a causative mutation, usually in one of these genes: ENG for HHT type 1, ACVRL1 for HHT type 2 and SMAD4 for juvenile polyposis-HHT overlap syndrome. Aims: The aim of the study was to perform a comprehensive clinical and genetic assessment in a family where at least the last six generations were suspicious of an HHT phenotype. Methods: Completing a family tree helped identify the inheritance pattern and the symptomatic cases (see attached). Some information was omitted since the available data was limited or irrelevant for the study, includying the sixth generation which only involved an asymptomatic newborn. Three young members –born in 1955, 1964 and 1985– were clinically diagnosed with HHT. They were referred to an HHT specialist and to an Otorhinolaryngologist with HHT expertise for evaluation and treatment. They were screened for iron deficiency anemia and for liver and pulmonary VM. They also received genetic counseling, instructions for antibiotic prophylaxis when undergoing dental procedures and anticoagulation advice when needed. A targeting exome analysis was performed on whole blood samples, covering five genes associated with HHT (ACVRL1, ENG, SMAD4, BMPR2, GDF2), in order to identify a causative mutation and to guide further studies in asymptomatic relatives. Results: The three symptomatic patients presented with spontaneous and recurrent epistaxis between the second and the fifth decade of life, with a tendency to progress with age and a negative impact on their quality of life. All of them have needed oral o intravenous iron supplementation at some point, two of them also requiring ablative therapies for nasal telangiectasia. Two of three patients are receiving full dose anticoagulants for atrial fibrillation, with no relevant worsening of the anemia. Only one of them had significant liver VM at diagnosis, that have not required any specific treatment to date. With regard to the genetic test, all three cases resulted to be heterozygous for an intronic variant in the ACVRL1 gene (c.752_772 + 2dup), consisting of a 23 nucleotide duplication in intron 6 splice donor site, that had not been previously described. Ten more samples were obtained from asymptomatic first degree relatives and the same variant was found in two of them –born in 1975 and 1994–. None of the negatives or their descendants have shown any bleeding symptoms. Summary/Conclusion: HHT is a rare condition with an autosomal dominant inheritance pattern and a high penetrance in late adulthood, so asymptomatic carriers could be considered at a presymptomatic stage of the disease. It usually affects several members of the same family with a negative impact on their quality of life, so its management should be multidisciplinary and family-focused. We have found a new variant in the ACVRL1 gene that seems to be consistent with an HHT-2 phenotype. It has been contrasted with different databases and in silico prediction tools, finding that its location in the gene could have an effect on ARNm processing and that the intronic variant c.772 + 3_772 + 4dupAA has been previously reported as pathogenic. The integration of clinical and genetical evidence supports the classification of this new variant as pathogenic.Keywords: Genetic, Bleeding disorder